The major aims of this project have been accomplished through the establishment of a large communitybased family study of adult probands who participate in comprehensive clinical and biologic assessments followed by comparable evaluations of their adult and child relatives. Recruitment of probands and evaluation of relatives are now near completion and analyses of the findings are underway. To date, over 500 probands and about 1000 of their relatives have completed the study, including over 150 children between the ages of 7-17. Approximately 500 completers have also been evaluated at the NIH Clinical Center. Probands represent a large range of disorders including mood, anxiety, sleep, migraine, and cardiovascular in addition to controls. We are now completing interviews with relatives who had not previously participated in the study. We have also begun to follow-up families in order to track health changes in child and adolescent relatives over time. In the past year, we have nearly completed analyses of the clinical phenomenology based on the best estimate diagnostic ratings and self-reported domains from the family study data. The most important finding from our analyses of family study data has been the unexpected independence of the familial aggregation of mania and major depression, the two major components of bipolar disorder (BPD) and that the familial aggregation of bipolar one (BPI) was primarily attributable to the familial specificity of manic episodes. Confirmation of these findings come from two of our studies in our Population-Based Epidemiologic Project: the parallel Family Study of Lausanne (Vandeleur et al, 2013) as well as in a prospective community sample from the Adolescent Supplement of the National Comorbidity Survey (NCS-A) dataset (Olfson et al, 2016). We also demonstrated the specificity of the familial aggregation of atypical and melancholic subtypes of depression and their clinical correlates (Lamers et al, 2016). In our evaluation of the specificity of familial links between the major anxiety disorder subtypes, we found that although there was specificity of panic disorder, social anxiety disorder and generalized anxiety disorder, the specificity was no longer significant after controlling for comorbid mood disorders. This confirms earlier family study and twin research demonstrating common diathesis underlying mood disorders, particularly major depression with anxiety disorders. There was a significant association between proband and relative hyperthymia. Of greater interest, probands and relatives with hyperthymia had significantly lower rates of nearly all mental and physical disorders than those without hyperthymia. These results support prior work indicating that hyperthymia may be protective against the full range of mental and physical conditions, and suggest that potential mechanisms should be further explored. A finding of a protective influence of a domain that has been postulated to lie on the same diathesis as mania and BPD, may confirm speculation that there may be an evolutionary advantage of the spectrum to affective temperament. We also examined the familiality of the temperamental traits including Positive and Negative affectivity, neuroticism anxiety, impulsivity, aggressivity, activity, and sociability, and found significant familial associations for temperamental traits including negative affectivity, anxious temperament, sociability, and anxiety sensitivity that persisted after control for anxiety and mood disorders. These results imply that anxiety-related temperamental traits are independent from clinical diagnoses and diagnostic subtypes. In summary, our preliminary analyses have converged in differentiating those with BPI from the other subtypes of mood disorders and/or controls in terms of variability of motor activity, rhythms of sleep and activity, greater cross-domain reactivity, and greater autonomic reactivity. Other measures tended to show non-specific differences across the range of mood disorder subtypes. Of importance, in contrast to most prior studies, we controlled for medication use that may influence many of these measures, and many of the probands were not taking medications at the time of the Clinical Center visit. Therefore, we now plan to focus on the BPI subtype to confirm and gain deeper understanding of these systems and their relationships. Publications cited: Lamers et al. Familial aggregation and heritability of the melancholic and atypical subtypes of depression. Journal of Affective Disorders. 2016 Jun 14. Vandeleur et al. Specificity of psychosis, mania and major depression in a contemporary family study. Molecular Psychiatry. 2013 Oct 15. Olfson et al. Reexamining associations between mania, depression, anxiety and substance use disorders: results from a prospective national cohort. Molecular Psychiatry. 2016 May 3. Public Health Impact: Integration of the clinical, neuropsychological and psychophysiological measures within families will render an in-depth analysis of the biological mechanisms crucial for mood and anxiety disorders and their underlying diatheses. This will not only lead to a better understanding of these conditions and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Future Plans: The initial findings of our study have major implications for etiology, treatment, course and nosology of mood and anxiety disorders. However, the work requires replication in larger samples, re-assessment to examine stability of the findings, and collaboration with other sites to cover the full range of the spectrum of mood disorders, and increase the power of the study. We therefore plan to double the number of probands with BPD in the study and conduct comprehensive examinations of the relatives, with a particular focus on youth ages 12-30. In the next year, we also plan to continue to follow-up the families already enrolled in the project to examine the stability of the findings, re-consent participants for sharing of genetic data, and repeat the mobile technologies measures to examine their fluctuation over time. Based on the findings from analyses of the study, we plan to design and pilot interventions that stabilize regulation of activity, sleep and other daily rhythms in this and other samples. We also plan to establish a collaborative network of affiliated studies of community, high risk and clinical samples of youth with common measures of mood and motor activity.